Women approaching advanced maternal age may have poor outcomes with both natural and assisted fertility (see e.g., Wen et al. Fertility and Sterility 2012). Moreover, the incidence of chromosomal abnormalities and birth defects increases with age. As of yet, there is no effective and practical strategy for delaying ovarian aging or improving oocyte quality.
Fertility in women is known to precipitously decline after the age of 35 (Schwartz D, Mayaux M J (1982), Female fecundity as a function of age: results of artificial insemination in 2193 nulliparous women with azoospermic husbands. Federation CECOS. N Engl J. Med. 306, 404-406), with fecundity being all but lost by the age of 45 (Ventura S J, Abma J C, Mosher W D, Henshaw S (2004). Estimated pregnancy rates for the United States, 1990-2000: an update. Natl Vital Stat Rep. 52, 1-9). With advancements in medical care, a woman's life expectancy has been prolonged by as much as 30 years over the past century while the age of menopause has changed by a meager 3-4 years during this same time period (Soules M R, Bremner W J (1982), The menopause and climacteric: endocrinologic basis and associated symptomatology. J Am Geriatr Soc. 30, 547-561). With this, an anomaly has been created in which the reproductive lifespan of women has become strikingly short in the context of overall lifespan, a discrepancy that is more pronounced today than ever before. The modern trend of postponing childbearing in this era of increased longevity, most notable in Western societies, brings the age-related decline in fertility to the forefront of scientific challenges in the field of reproductive medicine (Martin J A, Hamilton B E, Sutton P D, Ventura S J, Mathews T J, Kirmeyer S, Osterman M J (2010). Births: final data for 2007. Natl Vital Stat Rep. 58, 1-85).
Biologically, the age at which menopause occurs is determined by the progressive decline and ultimate depletion of the ovarian oocyte-containing follicle reserve (Hansen J P (1986). Older maternal age and pregnancy outcome: a review of the literature. Obstet Gynecol Surv. 41, 726-742; Faddy M J, Gosden R G, Gougeon A, Richardson S J, Nelson J F (1992). Accelerated disappearance of ovarian follicles in mid-life: implications for forecasting menopause. Hum Reprod. 7, 1342-1346; Tilly J L (2001). Commuting the death sentence: how oocytes strive to survive. Nat Rev Mol Cell Biol. 2, 838-848) concomitant with the diminishing quality of oocytes evidenced by an increase in chromosomal and spindle abnormalities and mitochondrial dysfunction (Battaglia D E, Goodwin P, Klein N A, Soules M R (1996). Influence of maternal age on meiotic spindle assembly in oocytes from naturally cycling women. Hum Reprod. 11, 2217-2222; Hunt P A, Hassold T J (2008). Human female meiosis: what makes a good egg go bad? Trends Genet. 24, 86-93; Selesniemi K, Lee H J, Muhlhauser A, Tilly J L (2011). Prevention of maternal aging-associated oocyte aneuploidy and meiotic spindle defects in mice by dietary and genetic strategies. Proc Natl Acad Sci USA. 108, 12319-12324). These changes significantly contribute to the poor success of natural and assisted fertility attempts for women of advanced reproductive age and to the increased incidence of chromosomal anomalies when conception is successful (Navot D, Bergh P A, Williams M A, Garrisi G J, Guzman I, Sandler B, Grunfeld L (1991b). Poor oocyte quality rather than implantation failure as a cause of age-related decline in female fertility. Lancet. 337, 1375-1377; van Kooij R J, Looman C W, Habbema J D, Dorland M, to Velde E R (1996). Age-dependent decrease in embryo implantation rate after in vitro fertilization. Fertil Steril. 66, 769-775). Similar to humans, laboratory rodents exhibit an age-related decline in ovarian follicle reserve leading to a state of natural infertility approximately halfway through their chronological lifespan (Gosden R G, Laing S C, Felicio L S, Nelson J F, Finch C E (1983). Imminent oocyte exhaustion and reduced follicular recruitment mark the transition to acyclicity in aging C57BL/6J mice. Biol Reprod. 28, 255-260; Perez G I, Robles R, Knudson C M, Flaws J A, Korsmeyer S J, Tilly J L (1999). Prolongation of ovarian lifespan into advanced chronological age by Bax-deficiency. Nat. Genet. 21, 200-203; Wu J M, Zelinski M B, Ingram D K, Ottinger M A (2005). Ovarian aging and menopause: current theories, hypotheses, and research models. Exp Biol Med (Maywood). 230, 818-828). Aging female mice exhibit many of the physiological changes observed in postmenopausal women, including the loss of cyclic ovarian function, making these animals an ideal in vivo model for the study of ovarian failure. Unfortunately, despite relevant rodent model systems and promising proposed strategies for prolonging the female reproductive lifespan (Perez G I, Robles R, Knudson C M, Flaws J A, Korsmeyer S J, Tilly J L (1999). Prolongation of ovarian lifespan into advanced chronological age by Bax-deficiency. Nat. Genet. 21, 200-203; Perez G I, Jurisicova A, Wise L, Lipina T, Kanisek M, Bechard A, Takai Y, Hunt P, Roder J, Grynpas M, Tilly J L (2007). Absence of the proapoptotic Bax protein extends fertility and alleviates age-related health complications in female mice. Proc Natl Acad Sci USA. 104, 5229-5234; Selesniemi K, Lee H J, Tilly J L (2008). Moderate caloric restriction initiated in rodents during adulthood sustains function of the female reproductive axis into advanced chronological age. Aging Cell. 7, 622-629; Selesniemi K, Lee H J, Niikura T, Tilly J L (2009). Young adult donor bone marrow infusions into female mice postpone age-related reproductive failure and improve offspring survival. Aging (Albany N.Y.). 1, 49-57; Niikura Y, Niikura T, Wang N, Satirapod C, Tilly J L (2010). Systemic signals in aged males exert potent rejuvenating effects on the ovarian follicle reserve in mammalian females. Aging (Albany N.Y.). 2, 999-1003; Selesniemi K, Lee H J, Muhlhauser A, Tilly J L (2011). Prevention of maternal aging-associated oocyte aneuploidy and meiotic spindle defects in mice by dietary and genetic strategies. Proc Natl Acad Sci USA. 108, 12319-12324), an effective and realistic strategy for significantly delaying ovarian aging or improving oocyte quality has yet to be developed.
Changes in the dietary patterns of humans over time may provide insight into novel avenues for delaying ovarian aging. Anthropological and nutritional studies demonstrate a remarkable change in the human diet over the past 100 years, most notably with regard to the type and amount of fat consumed (Eaton S B, Konner M (1985). Paleolithic nutrition. A consideration of its nature and current implications. N Engl J. Med. 312, 283-289; Simopoulos A P (1991). Omega-3 fatty acids in health and disease and in growth and development. Am J Clin Nutr. 54, 438-463; Simopoulos A P (2003). Importance of the ratio of omega-6/omega-3 essential fatty acids: evolutionary aspects. World Rev Nutr Diet. 92, 1-22; Simopoulos A P (2006). Evolutionary aspects of diet, the omega-6/omega-3 ratio and genetic variation: nutritional implications for chronic diseases. Biomed Pharmacother. 60, 502-507; Simopoulos A P (2009). Evolutionary aspects of the dietary omega-6:omega-3 fatty acid ratio: medical implications. World Rev Nutr Diet. 100, 1-21; Simopoulos A P (2011). Importance of the omega-6/omega-3 balance in health and disease: evolutionary aspects of diet. World Rev Nutr Diet. 102, 10-21). These changes are manifested by both an absolute and a relative change in the omega-6 and omega-3 fatty acid consumption. Today, the Western diet provides an omega-6 to omega-3 fatty acid ratio of as high as 25:1, which is in stark contrast to the 1:1 ratio historically consumed by humans (Simopoulos A P (2006). Evolutionary aspects of diet, the omega-6/omega-3 ratio and genetic variation: nutritional implications for chronic diseases. Biomed Pharmacother. 60, 502-507), creating a nutritional environment that is different from our ancestors and from which our genetic constitution was selected. This change is particularly relevant given that the shift in dietary habits over the last 100 years is accompanied by a concurrent downward trend in the fertility rates for women over the age of 35 (Baird D T, Collins J, Egozcue J, Evers L H, Gianaroli L, Leridon H, Sunde A, Templeton A, Van Steirteghem A, Cohen J, Crosignani P G, Devroey P, Diedrich K, Fauser B C, Fraser L, Glasier A, Liebaers I, Mautone G, Penney G, Tarlatzis B (2005). Fertility and ageing. Hum Reprod Update. 11, 261-276).
It is disclosed herein that the consumption omega-3 fatty acids may prolong murine reproductive function into advanced maternal age, while a diet rich in omega-6 fatty acids may be associated with poor reproductive success at advanced maternal age. Furthermore, even short-term consumption of omega-3 fatty acids initiated at the time of the normal age-related rapid decline in murine reproductive function may be associated with improved oocyte quality, while short-term consumption of omega-6 fatty acids may result in poor oocyte quality. Thus, omega-3 fatty acids may provide an effective and practical avenue for delaying ovarian aging and improving oocyte quality at advanced maternal age.